ASCO Updates First-Line Treatment for Stage 4 EGFR Lung Cancer

The American Society of Clinical Oncology (ASCO) released updated treatment recommendations for patients with stage 4 non-small cell lung cancer that has specific genetic changes.

These new guidelines, published in the Journal of Clinical Oncology, provide a roadmap for using newer combination therapies as the first treatment for patients whose cancer has certain mutations, such as those in the EGFR gene. By incorporating the latest data from 13 clinical studies, the expert panel aims to help patients with cancer and their healthcare teams choose the most effective treatment options based on the unique genetic signature of their tumor.

Understanding the latest treatment data

The updated guidelines emphasize that for patients with stage IV non-small cell lung cancer and certain EGFR mutations, starting treatment with a combination of drugs may be more effective than using a single drug. In one major study known as FLAURA2, patients with cancer who received a combination of Tagrisso (osimertinib), and chemotherapy lived a median of 25.5 months without their disease getting worse, compared to 16.7 months for those who received only Tagrisso. Another study, MARIPOSA, showed that a combination of Rybrevant (amivantamab) and Lazcluze (lazertinib) resulted in a 60% survival rate at three years, compared to 51% for patients who took Tagrisso alone.

For patients whose cancer has an EGFR exon 20 insertion mutation, the guidelines now recommend a combination of chemotherapy and Rybrevant. This recommendation is supported by clinical findings where adding Rybrevant to chemotherapy reduced the risk of the cancer progressing compared to chemotherapy alone. These findings suggest that intensifying the first line of treatment can lead to longer periods of disease control for many patients across different genetic profiles.

Details of the clinical trials

The new recommendations are based on a review of evidence identified through routinely scheduled searches of phase 3 randomized controlled trials.

• The FLAURA2 trial included 557 patients with previously untreated metastatic non-small cell lung cancer and EGFR mutations.
• Patients in FLAURA2 were assigned to receive either 80 mg of Tagrisso daily plus platinum-based chemotherapy every three weeks, or 80 mg of Tagrisso daily as a single treatment.
• The MARIPOSA trial studied 1,074 patients who were assigned to receive Rybrevant and Lazcluze, Tagrisso alone, or Lazcluze alone.
• In the combination group of MARIPOSA, patients received Rybrevant through an IV once a week for four weeks and then every two weeks, along with 240 mg of Lazcluze by mouth every day.
• The PAPILLON trial focused on patients with EGFR exon 20 insertion mutations, comparing the combination of Rybrevant and chemotherapy to chemotherapy alone.
• For patients with cancer that has spread to the brain, both the FLAURA2 and MARIPOSA trials showed that the combination treatments provided better results than a single drug.

Side effects and safety considerations

While combination therapies can be more effective, they are also associated with more side effects than single-drug treatments.

• In the trial testing Tagrisso with chemotherapy, 64% of patients had side effects that were considered grade 3 or higher, compared to 27% of those taking only Tagrisso.
• The most common side effects for the Tagrisso and chemotherapy combination included anemia at 46%, diarrhea at 43%, and nausea at 43%.
• In the trial for Rybrevant and Lazcluze, 75% of patients experienced side effects of grade 3 or higher.
• Common side effects for the Rybrevant and Lazcluze combination included a skin infection around the nails called paronychia at 68%, reactions related to the IV infusion at 63%, and skin rash at 62%.
• Other reported side effects for these treatments include low protein levels in the blood, increased liver enzymes, swelling in the arms or legs, and mouth sores.
• Clinicians are advised to balance the survival benefits of these combinations against the increased side effects and treatment frequency.

References

1. “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, 2026.3.0” by Dr. Sonam Puri, et al., Journal of Clinical Oncology.

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